Neoplastic diseases in humans are recognized throughout the world as being serious and oftentimes life-threatening conditions. These neoplastic diseases, which are characterized by rapidly-proliferating cell growth, have been and continue to be the subject of worldwide research efforts directed toward the identification of therapeutic agents which are effective in the treatment of patients suffering therefrom. Effective therapeutic agents can be characterized as those which prolong the survival of the patients, which inhibit the rapidly-proliferating cell growth associated with the neoplasm, or which effect a regression of the neoplasm. Research in this area is primarily focused toward identifying agents which would be therapeutically effective in humans. Typically, compounds are tested for antineoplastic activity in small mammals, such as mice, in experiments designed to be predictive of antineoplastic activity not only in those animals but also in humans against specific neoplastic disease states. The present invention concerns a method for treating tumors utilizing a combination of known antitumor agents which exert their efficacy through inhibition of tumor cells proliferation (cytotoxic agents) with known not-cytotoxic ureido compounds which exert their efficacy through inhibition of blood vessel formation (angiogenesis).
It is a recognized phenomenon that angiogenesis is a fundamental requisite for solid tumor growth and metastatic spread. Angiogenesis is started when tumor cells produce angiogenic factors which stimulate quiescent endothelial cells to proliferate, destroy the basal membrane, migrate, adhere and proliferate to form new capillaries. As a consequence, inhibitors of angiogenesis will block tumor growth; although no definitive clinical response is presently available on the activity of the angiogenesis inhibitors undergoing clinical trials, experimental evidence indicates that modulation of angiogenesis alone may be insufficient to efficiently control tumor growth and metastatic spread. It is thus conceivable that combined therapy with non toxic inhibitors of angiogenesis and cytotoxic agents can represent a new effective clinical regimen.
Biologically active compounds known from WO 91/10649 inhibit angiogenesis through making a complex with growth factors and angiogenic polypeptides such as basic fibroblast growth factor, insulin growth factor-1 and hepatocyte growth factor. They do not inhibit tumor cells proliferation, and administered by intravenous (iv), intraperitoneal (ip), subcutaneous (sc) and oral route inhibit in mice angiogenesis induced by growth/angiogenic factors and the growth of transplanted human and murine tumors.
It has now been found that in treating a patient affected with certain neoplastic disease states, conjunctive therapy with a biologically active compound known from WO 91/10649 and a cytotoxic agent, will provide a synergistic antineoplastic effect.
A synergistic effect is achieved when a greater antineoplastic effect results with a conjunctive therapy than use of either drug alone, thus giving a superadditive antineoplastic effect. One advantage of conjunctive therapy with a synergistic effect is that lower dosages of the antineoplastic agent may be used so that the therapeutic index is increased and toxic side effects are reduced.